title: Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce α-synuclein phosphorylation in rat brain.
abstract: Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.
authors.affiliation: Molecular Discovery, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Aubele
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: Hu
authors.initials: H
authors.lastname: Pan
authors.forename: Paul
authors.initials: P
authors.lastname: Beroza
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: May
authors.initials: M
authors.lastname: Lin
authors.forename: George
authors.initials: G
authors.lastname: Tonn
authors.forename: Heather
authors.initials: H
authors.lastname: Zhang
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bova
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
authors.forename: Danny
authors.initials: D
authors.lastname: Tam
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Jeanne
authors.initials: J
authors.lastname: Baker
authors.forename: Linnea
authors.initials: L
authors.lastname: Diep
authors.forename: Kent
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hoffman
authors.forename: Ruth
authors.initials: R
authors.lastname: Motter
authors.forename: Donald
authors.initials: D
authors.lastname: Fauss
authors.forename: Pearl
authors.initials: P
authors.lastname: Tanaka
authors.forename: Michael
authors.initials: M
authors.lastname: Dappen
authors.forename: Jacek
authors.initials: J
authors.lastname: Jagodzinski
authors.forename: Wayman
authors.initials: W
authors.lastname: Chan
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Lee
authors.initials: L
authors.lastname: Latimer
authors.forename: Yong L
authors.initials: YL
authors.lastname: Zhu
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: John P
authors.initials: JP
authors.lastname: Anderson
authors.forename: Marcelle
authors.initials: M
authors.lastname: Bergeron
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
mesh_terms: D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; C530504:Plk2 protein, rat
keywords: Parkinson’s disease; computational chemistry; kinase inhibitors; medicinal chemistry; polo-like kinase-2